The invention relates to novel cyclic urea compounds useful in enhancing drug absorption through the skin. More specifically, the invention relates to said urea compounds being useful as penetration enhancers in topical compositions comprising an effective amount of a therapeutic agent. Also, the invention relates to processes for preparing said novel compounds.
Although there has been a greatly expanded recent interest in percutaneous drug deliver, efforts in this direction have been limited by the fact that most drug substances are poorly absorbed through the skin. This situation has recently led to a number of programs directed towards development of agents which would behave as enhancers of dermal absorption. Out of these studies a number of potential absorption promoters have been identified. These include dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), some surface-active agents, 2-pyrrolidone, N,N-diethyl-m-toluamide (Deet) and Azone.RTM.0 (1-dodecylazacycloheptane-2-one). Although most of these candidates have been shown to be effective in increasing the rate of drug transfer across the skin, their use has been limited in that very few dermal preparations containing them have actually reached the marketplace. This has probably been due to the real or imagined fear of their use leading to some undesired localized damage to the skin or to systemic toxicity. Of this group, only Deet has had a significant history of being applied to the skin, but as an insect repellent, rather than, an absorption adjuvant.
In spite of the fact that so many compounds have been evaluated for their effect on enhancing dermal penetration of drugs, the mechanism of enhancement and the controlling of physicochemical properties are still not well understood. One property which has been reportedly mentioned is the hydrogen bonding abilities of the effective enhancers. The conclusion is based on the known effectiveness of hydrogen accepting agents such as DMSO and DMA as absorption promoters. Since these solvents are known as strong hydrogen bonding acceptors, their hydrogen bonding abilities were considered to relate to their effectiveness as dermal penetration enhancers.